Treatments for nervous disorders

ABSTRACT

This patent application describes the treatment of Addictive disorders, Psychoactive Substance Use disorders, Intoxication disorders, Inhalation disorders, Alcohol addiction, Tobacco addiction and or Nicotine addiction; and Attention Deficit Hyperactivity Disorder (ADHD); comprising administering a therapeutically effective, nontoxic dose of Reboxetine and derivatives and or pharmaceutically acceptable salts thereof to a patient.

FIELD OF THE INVENTION

[0001] This invention describes new treatments for several nervoussystem disorders, including: Addictive Disorders, Psychoactive SubstanceUse Disorders, Nicotine Addiction or Tobacco Addiction resulting inSmoking Cessation and Attention Deficit Hyperactivity Disorder (ADHD).The treatment involves the administration of the drug Reboxetine to apatient in need.

BACKGROUND

[0002] The introduction of tricyclic antidepressants in the early 1960shas provided a major advance in the treatment of neuropsychiatricdisorders. Reactive and endogenous depressions, diagnoses formerlycarrying grave prognostic implications, have become, with theintroduction of the tricyclics, manageable disorders with a much smallertoll on the patient and the society as a whole. Electroconvulsive ShockTherapy once the only efficacious treatment in spite of its highlyinvasive nature, has now become, thanks to tricyclics, an obsolete formof treatment in most Countries.

[0003] The early tricyclic compounds were reuptake inhibitors of all thecatecholaminies released in the synaptic cleft, thus resulting inprolongation and enhancement of the dopamine (DA), noradrenaline (NA)and serotonin (5-hydroxytrypramine=5-HT) action. Desipramine, forexample, has been characterized as “one of the most studied of thetricyclic anti-depressants in ADHD children and adolescents.” T. E.Wilens, et al. Am. J. Psychiatry 153:1147-1153, 1148 (1996). It has alsobeen considered as a treatment for the disease in adults. Id.Unfortunately, a lack of selectivity for most tricyclics, includingdesipramine can also cause undesired side effects particularly on theacetylcholine (especially the muscarinic component), and histaminemediated neurotransmission.

[0004] Because of these unwanted pharmacodynamic activities, cognitiveimpairment, sedation, urinary and gastrointestinal tract disturbances,increased intraocular pressure were limiting factors in the clinical useof these compounds and often required discontinuation of treatment. Ofutmost concern were also the cardiac toxic effects and the proconvulsantactivity of this group of drugs.

[0005] Another drug, methylphenidate, is also known to have clinicalefficacy for the treatment of ADHD. Wender, P. H., et al. Am. J.Psychiatry 142:547-552 (1985).

[0006] More recently, selective reuptake inhibitors for serotonin (SSRI)have been introduced with definite advantages in regard to fewer sideeffects without loss of efficacy.

[0007] Here we present the surprising finding that one particular drugfrom a new category of antidepressants, a so called noradrenaline (NA)reuptake inhibitor can be used to manage or treat a few specialdiseases, diseases having symptoms outside of what are usuallyconsidered depression symptoms. Now these diseases may be treated withReboxetine.

SUMMARY OF THE INVENTION

[0008] This patent application describes the treatment of AddictiveDisorders, Psychoactive Substance Use Disorders, Nicotine Addition orTobacco Addiction (with a result of Smoking Cessation or a decrease insmoking) and Attention Deficit Hyperactivity Disorder (ADHD), comprisingadministering a therapeutically effective nontoxic dose of Reboxetineand derivatives and or pharmaceutically acceptable salts thereof to apatient.

[0009] Reboxetine is the generic name of the pharmaceutical substancewith the chemical name of 2-(1-((2-ethoxyphenoxy)benzyl)-morpholine, andits pharmaceutically acceptable salts. Reboxetine can be a free base, orit can include reboxetine methanesulfonate (also called reboxetinemesylate) or any other pharmaceutically acceptable salt that does notsignificantly affect the pharmaceutical activity of the substance.

[0010] A preferred dose range is 4 to 10 mg per patient per day and themost preferred dose is 6 to 8 mg or 8 to 10 mg per patient daily,depending upon the patient, delivered twice a day (b.i.d.).

ADDITIONAL DESCRIPTION OF THE INVENTION AND DESCRIPTION OF THE PREFERREDEMBODIMENTS

[0011] Reboxetine is the generic name of the pharmaceutical substancewith the chemical name of 2-(1-((2-ethoxyphenoxy)benzyl)-morpholine, andits pharmaceutically acceptable salts. Reboxetine can be a free base, orit can include reboxetine methanesulfonate (also called reboxetinemesylate) or any other pharmaceutically acceptable salt that does notsignificantly affect the pharmaceutical activity of the substance.Reboxetine and a method of synthesis are described in U.S. Pat. No.4,229,449, issued Oct. 21, 1980, Melloni et. al., incorporated byreference, methods of preparation are described U.S. Pat. No. 5,068,433,issued Nov. 26, 1991, Melloni et. al. and in U.S. Pat. No. 5,391,735,issued Feb. 21, 1995, both incorporated by reference. Reboxetine mayalso be known under the trade name of EDRONAX™.

[0012] The pharmaceutical compositions and methods of administrationdescribed in U.S. Pat. No. 4,229,449 at col. 18, lines 33-66 arespecifically incorporated by reference. Twice a day dosing is preferredwith current formulations.

[0013] Reboxetine acts as an antidepressant. Antidepressants arefrequently grouped into categories or “generations.” The firstgeneration of antidepressants were usually tricyclic antidepressantssuch as maprotiline that affected various neurotransmitter systems andare associated with many undesirable side effects. The second generationof antidepressants, such as mianserine, mirtrazapine and trazodone arelargely devoid of anticholinergic action and their adrenolytic andantihistaminic effects are weaker. These are contrasted with the thirdgeneration of antidepressants (e.g. SSRI, ipsapirone, viloxazine,reboxetine, bupropione) that mediate only one of the three mainneurotransmitter system for depression (5-HT, noradrenaline, dopamine)and they do not affect muscarine, histamine and adrenergic cerebralsystems. Svestka, J. “Antidepressives of the 3rd, 4th and 5thgeneration,” Cesk-Psychiatr. February 1994; 90(1):3-19. (Czech).

[0014] Reboxetine however; does not act like most antidepressants.Unlike tricyclic antidepressants and even selective serotonin reuptakeinhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAThypothermia test, indicating that reboxeitne is not a selectiveserotonin reuptake inhibitor rather it is selective for thenoradrenergic system. Thus, reboxetine is not an SSRI, rather it isconsidered a novel, selective, noradrenaline-reuptake inhibitor (NARI).Leonard-BE, “Noradrenaline in basic models of depression.”European-Neuropsychopharmacol. April 1997; 7 Suppl 1: S11-6; discussionS71-3. Unlike most drugs, Reboxetine is a highly selectivenorepinephrine uptake inhibitor, with only marginal serotonin and nodopamine uptake inhibitory activity. The compound displays only weak orno anti-cholinergic activity in different animal models and is devoid ofmonoamine oxidase (MAO) inhibitory activity.

[0015] Reboxetine is highly potent and fast acting. Our investigationsindicate Reboxetine has potent antireserpine activity and combines theinhibitory properties of classical tricyclic antidepressants on thereuptake of noradrenaline with an ability to desensitize J-adrenergicreceptor function without showing any appreciable interaction withmuscarinic cholinergic and I-adrenerigic receptors. Moreover, Reboxetineshows less vagolytic activity than other tricyclic antidepressants.

[0016] The inventors have discovered that, because of its uniqueproperties, Reboxetine has been found particularly useful for treatingor enhancing the treatment of a few psychiatric symptoms or disorders,with greater efficacy and with fewer side effects, than are treated byknown drugs. Furthermore, the inventors here have also discovered thatReboxetine can also be used to treat or to enhance the treatment of afew other specific psychiatric symptoms or disorders. The symptoms ordisorders amenable to treatment with Reboxetine are provided below.

[0017] The dosage used to treat all of the disorders described here isas follows. Reboxetine is well tolerated and has a wide safety range, itcan be administered in a dose range of active ingredient from about 1 toover 20 mg/kg. It is more commonly provided in dosages of from 1 to 20mg per patient per day. The compound may be administered by any suitablemethod including a convenient oral dosage form. A preferred method isoral dosing twice a day. The preferred dose range is 4 to 10 mg perpatient per day and the most preferred dose is 6 to 8 mg or 8 to 10 mgper patient daily, depending upon the patient, delivered twice a day(b.i.d.). It can also be given at dosages of 2, 4, 6, 8, 10 or 12 mg perpatient per day or fractions thereof: For example, suitableadministrations could be 4 mg in the morning and 2 or 4 mg in theevening or 6 mg in the morning and 4 mg in the evening. In some patientsthe ideal dosing would be 3-5 mg in the morning and 3-5 mg in theevening. A skilled practitioner would be expected to determine theprecise level of dosing. The ideal dosing would be routinely determinedby an evaluation of clinical trials and the needs of the patient.

[0018] The diseases described for treatment here are:

[0019] I. Addictive Disorders and Psychoactive Substance Use Disorders,such as Intoxication Disorders, Inhalation Disorders, Alcohol Addiction,Tobacco Addiction and or Nicotine Addiction. Tobacco and NicotineAddiction would be Treated with the Goal of Achieving either SmokingCessation or Smoking Reductions.

[0020] Addictive Disorders, Alcohol and Other Psychoactive Substance UseDisorders, disorders related to Intoxication and Inhalants andespecially Tobacco Addiction or Nicotine Addiction, may be treated withReboxetine. Tobacco Addiction or Nicotine Addiction would be treatedwith Reboxetine in order to achieve smoking/chewing cessation orsmoking/chewing reduction. General descriptions of Addictive Disorders,including disorders related to Intoxication and Inhalants and TobaccoAddiction or Nicotine Addiction may be found in many standard sources,such as, The American Psychiatric Press Textbook of Psychiatry, SecondEdition, Edited by Robert E. Hales, Stuart C. Yudofsky, and John A.Talbott, copyright 1994, incorporated by reference, especially pp. 401et. seq., section on “Nicotine” incorporated by reference. Another ofmany texts is the Manual of Psychiatric Therapeutics, Second Edition,edited by Richard I. Shader, incorporated by reference, especially pp.85 from Chapter 11 (Hypnosis).

[0021] The treatment of Alcohol and Other Psychoactive Substance UseDisorders, such as disorders related to Intoxication and Inhalants andTobacco Addiction or Nicotine Addiction but especially Tobacco Addictioninvolves the administration of Reboxetine in a manner and form thatprovide a reduction in the symptoms of the disease. Tobacco Addiction orNicotine Addiction in particular would be treated to achieve a reductionor cessation of smoking or chewing of nicotine containing materials by apatient. Cessation or a reduction in smoking or chewing of addictive orpsychoactive substances involves the administration of Reboxetine in amanner and form that provide a reduction in the symptoms of the disease,or with Tobacco or Nicotine with a reduction in the amount smoked orchewed. See the general description above for administration ofReboxetine.

[0022] II. Attention Deficit Hyperactivity Disorder (ADHD).

[0023] ADHD is a condition or disease state that may be treated withReboxetine. General descriptions of ADHD, may be found in many standardsources, such as The American Psychiatric Press Textbook of Psychiatry,Second Edition, Edited by Robert E. Hales, Stuart C. Yudofsky, and JohnA. Talbott, copyright 1994, incorporated by reference, especially pp.741 et. al., section on “ADHD,” incorporated by reference. Another ofmany texts is the Manual of Psychiatric Therapeutics, Second Edition,edited by Richard I. Shader, incorporated by reference, especiallyChapter 18, Attention-Deficit hyperactivity Disorder, and pp. 172 et.seq., incorporated by reference.

[0024] The treatment of Attention Deficit Hyperactivity Disorder inchildren and adults involves the administration of Reboxetine in amanner and form that provide a reduction in the symptoms of the disease.A child or young adult may require a smaller dosage depending upon thesize, age, condition of the patient. See general description above foradministration of Reboxetine.

1. A method of treating or enhancing the treatment of a disorderselected from: a) Addictive Disorders, Psychoactive Substance UseDisorders, Intoxication disorders, Inhalation disorders, Alcoholaddiction, Tobacco Addiction and or Nicotine Addiction; and b) AttentionDeficit Hyperactivity Disorder (ADHD); comprising administering atherapeutically effective, nontoxic dose of Reboxetine and derivativesand or pharmaceutically acceptable salts thereof to a patient.
 2. Themethod of claim 1 where Reboxetine is used to treat or enhance thetreatment of Tobacco and or Nicotine Addiction.
 3. The method of claim 2where Reboxetine is used to reduce the craving for Tobacco or Nicotinecontaining products.
 4. The method of claim 2 where Reboxetine is usedto reduce the smoking or chewing of Tobacco or Nicotine containingproducts.
 5. The method of claim 1 where Reboxetine is used to treat orenhance the treatment of Attention Deficit Hyperactivity Disorder(ADHD).
 6. The method of claim 5 where Reboxetine is used to increasethe attention span and calm individuals afflicted with ADHD.
 7. A methodfor treating or enhancing the treatment of a disorder selected from: a)Addictive Disorders, Psychoactive Substance Use Disorders, Intoxicationdisorders, Inhalation disorders, Alcohol addiction, Tobacco Addictionand or Nicotine Addiction; and p1 b) Attention Deficit HyperactivityDisorder (ADHD); comprising administering a therapeutically effective,nontoxic dose of Reboxetine and derivatives and or pharmaceuticallyacceptable salts thereof to a patient in need of an effective treatmentthereof.
 8. The use of Reboxetine or its pharmaceutically acceptablesalts in the manufacture of a medicament to treat: a) AddictiveDisorders, Psychoactive Substance Use Disorders, Intoxication disorders,Inhalation disorders, Alcohol addiction, Tobacco Addiction and orNicotine Addiction; and b) Attention Deficit Hyperactivity Disorder(ADHD); and for any of the symptoms of any of those diseases.
 9. Themethod or use in claims 1-8 where the reboxetine dose range is 4 to 10mg. per patient per day.
 10. The method or use in claims 1-8 where thereboxetine dose range is 6 to 8 mg. per patient per day.